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Epigenetic control of alveolar fluid clearance

Epigenetische Kontrolle der alveolären Flüssigkeitsklärung

Wujak, Lukasz Andrzej

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URN: urn:nbn:de:hebis:26-opus-114406

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Universität Justus-Liebig-Universität Gießen
Institut: Max-Planck-Institute for Heart and Lung Research
Fachgebiet: Medizin
DDC-Sachgruppe: Medizin
Dokumentart: Dissertation
Sprache: Englisch
Tag der mündlichen Prüfung: 12.06.2014
Erstellungsjahr: 2014
Publikationsdatum: 15.04.2015
Kurzfassung auf Englisch: Acute respiratory distress syndrome (ARDS) is a devastating disease characterized by high mortality with no available pharmacological therapy. Transforming growth factor (TGF)-beta mediates ARDS by promoting formation and persistence of alveolar edema. The deregulation of the Na,K-ATPase, a key Na+ transporter in the alveolar epithelium, has been reported in ARDS, where impaired Na,K-ATPase function perturbs alveolar fluid clearance (AFC). In the present study, downregulation of ATP1B1, a gene encoding an essential subunit of the Na,K-ATPase, has been observed in ARDS patients, bleomycin model of ARDS and in TGF-beta-treated primary mouse alveolar epithelial type II cells and A549 cells. A mechanism of TGF-beta-regulated repression of the ATP1B1 gene relied on SMAD2, SMAD4, SNAI1 and E2F5 transcription factors. Moreover, epigenetic machinery involving DNA methylation and action of histone deacetylases (HDAC) have been found to mediate the TGF-beta-controlled downregulation of the ATP1B1 gene. The class I HDAC member, HDAC2, has been identified as a critical element involved in ATP1B1 gene repression, and has been observed to bind the ATP1B1 promoter and to be activated by TGF-beta signaling. The treatment with the histone deacetylase inhibitor trichostatin A (TSA) rescued expression of the Atp1b1 gene in the bleomycin model of ARDS which was accompanied by decreased lung wet-to-dry ratio. However, TSA neither decreased alveolar-capillary barrier permeability nor alleviated inflammatory responses indicating that reduction of edema was attributable to restored Na+ transport and increased AFC.
These data describe a novel system of HDAC-regulated repression of the Atp1b1 gene by TGF-beta which could be targeted and disrupted by HDAC inhibition in the bleomycin model of ARDS. Therefore, this study provides strong evidence to support the use of HDAC inhibitors in pharmacological therapy of ARDS.
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